COVID-19 Vaccines: A Comprehensive Review of Short-term and Long-term Adverse Effects

Introduction

The rapid development and deployment of vaccines against SARS-CoV-2, the virus that causes COVID-19, has been a remarkable scientific achievement. Several vaccines, including mRNA vaccines (Pfizer-BioNTech and Moderna), viral vector vaccines (AstraZeneca and Janssen), and inactivated virus vaccines (Sinovac and Sinopharm), have been authorized for emergency use and administered to millions of people worldwide (1). While these vaccines have demonstrated high efficacy in preventing symptomatic COVID-19, concerns have been raised about their potential short-term and long-term adverse effects.

This review article aims to summarise the current evidence on the adverse effects of COVID-19 vaccines, focusing on both short-term reactogenicity and long-term safety concerns. We will discuss the mechanisms behind these adverse effects, their incidence rates, and the challenges in assessing long-term safety. Finally, we will provide recommendations for future research and surveillance to ensure the continued safety of COVID-19 vaccines.

Short-term adverse effects

Local reactions

The most common short-term adverse effects of COVID-19 vaccines are local reactions at the injection site, such as pain, redness, and swelling. These reactions are typically mild and resolve within a few days (2). In clinical trials, local reactions were reported by 60-90% of participants, with higher rates in younger age groups and after the second dose (3,4,5).

The mechanisms behind local reactions are thought to involve the activation of innate immune responses, such as the release of pro-inflammatory cytokines and the recruitment of immune cells to the injection site (6). These responses are a normal part of the body’s defense against foreign antigens and are not considered a cause for concern.

Systemic reactions

Systemic reactions, such as fever, fatigue, headache, and muscle pain, are also common short-term adverse effects of COVID-19 vaccines. These reactions are more frequent and severe after the second dose and in younger age groups (3,4,5). In clinical trials, systemic reactions were reported by 30-80% of participants, with fever being the least common symptom (2).

The mechanisms behind systemic reactions are similar to those of local reactions, involving the activation of innate immune responses and the release of pro-inflammatory cytokines (6). These responses can cause flu-like symptoms and are a sign that the immune system is responding to the vaccine.

Allergic reactions

Allergic reactions, including anaphylaxis, have been reported after the administration of COVID-19 vaccines, particularly the mRNA vaccines (7). Anaphylaxis is a severe, potentially life-threatening allergic reaction that can cause difficulty breathing, hives, and low blood pressure (8). The incidence of anaphylaxis after COVID-19 vaccination is estimated to be 2.5-4.7 cases per million doses, which is higher than the rate for other vaccines (9).

The mechanisms behind vaccine-induced anaphylaxis are thought to involve the activation of mast cells and basophils, which release histamine and other mediators (10). The specific components of COVID-19 vaccines that trigger these reactions are not yet fully understood, but they may include the polyethylene glycol (PEG) in mRNA vaccines or the polysorbate 80 in viral vector vaccines (11).

Thrombosis with thrombocytopenia syndrome (TTS)

Thrombosis with thrombocytopenia syndrome (TTS) is a rare but serious adverse effect that has been reported after the administration of the AstraZeneca and Janssen viral vector vaccines (12). TTS is characterized by the formation of blood clots in unusual locations, such as the cerebral veins or splanchnic veins, accompanied by low platelet counts (13). The incidence of TTS after viral vector vaccination is estimated to be 1-2 cases per 100,000 doses, with higher rates in younger age groups and after the first dose (14).

The mechanisms behind TTS are not yet fully understood, but they are thought to involve the development of antibodies against platelet factor 4 (PF4), which causes platelet activation and aggregation (15). These antibodies are similar to those seen in heparin-induced thrombocytopenia (HIT), but they occur in the absence of heparin exposure (16). The specific components of viral vector vaccines that trigger the formation of these antibodies are not yet known.

Guillain-Barré syndrome (GBS)

Guillain-Barré syndrome (GBS) is a rare neurological disorder that has been reported as a potential adverse effect of COVID-19 vaccines, particularly the AstraZeneca and Janssen viral vector vaccines (17). GBS is characterized by weakness and tingling in the extremities, which can progress to paralysis (18). The incidence of GBS after COVID-19 vaccination is estimated to be 1-2 cases per 100,000 doses, which is similar to the background rate in the general population (19).

The mechanisms behind vaccine-induced GBS are not yet fully understood, but they are thought to involve an autoimmune response against peripheral nerve antigens, such as gangliosides (20). This response may be triggered by molecular mimicry, where the immune system mistakes self-antigens for foreign antigens due to structural similarities (21). The specific components of COVID-19 vaccines that trigger this response are not yet known.

Long-term adverse effects

Autoimmune diseases

The potential for COVID-19 vaccines to trigger or exacerbate autoimmune diseases has been a concern, given the known association between infections and autoimmunity (22). However, to date, there is no evidence of an increased risk of autoimmune diseases after COVID-19 vaccination (23). In fact, some studies have suggested that COVID-19 vaccines may have a protective effect against autoimmune diseases, by reducing the risk of SARS-CoV-2 infection and the associated immune dysregulation (24).

The mechanisms behind the potential link between COVID-19 vaccines and autoimmunity are complex and not yet fully understood. On the one hand, the activation of innate and adaptive immune responses by vaccines could potentially trigger autoimmune reactions in genetically susceptible individuals (25). On the other hand, vaccines could also have a protective effect against autoimmunity, by inducing a more balanced and regulated immune response compared to natural infection (26).

Antibody-dependent enhancement (ADE)

Antibody-dependent enhancement (ADE) is a phenomenon where the presence of antibodies against a virus can enhance its entry into host cells and exacerbate the severity of the disease (27). The potential for ADE after COVID-19 vaccination has been a concern, given the known occurrence of ADE in other viral infections, such as dengue fever (28). However, to date, there is no evidence of ADE after COVID-19 vaccination, either in clinical trials or in real-world data (29).

The mechanisms behind ADE are complex and involve the interaction between virus-specific antibodies and Fc receptors on host cells (30). In the case of COVID-19, it has been hypothesized that antibodies against the spike protein could potentially enhance the entry of SARS-CoV-2 into cells expressing Fc receptors, such as macrophages and dendritic cells (31). However, this hypothesis has not been supported by experimental evidence, and the specific epitopes and antibody classes involved in ADE remain unknown (32).

Vaccine-associated enhanced respiratory disease (VAERD)

Vaccine-associated enhanced respiratory disease (VAERD) is a phenomenon where vaccination against a respiratory virus can lead to more severe disease upon subsequent infection with the same or a related virus (33). The potential for VAERD after COVID-19 vaccination has been a concern, given the known occurrence of VAERD in other respiratory infections, such as respiratory syncytial virus (RSV) (34). However, to date, there is no evidence of VAERD after COVID-19 vaccination, either in animal models or in human studies (35).

The mechanisms behind VAERD are not yet fully understood, but they are thought to involve a dysregulated immune response, characterized by the production of non-neutralizing antibodies and the activation of Th2-biased T cell responses (36). These responses can lead to increased inflammation and tissue damage in the lungs upon subsequent infection (37). The specific components of COVID-19 vaccines that could potentially trigger VAERD are not yet known, but they may include the choice of antigen, adjuvant, or delivery system (38).

Long-term effects on fertility and pregnancy

The potential long-term effects of COVID-19 vaccines on fertility and pregnancy have been a concern, given the lack of data on these outcomes in the initial clinical trials (39). However, to date, there is no evidence of any adverse effects of COVID-19 vaccines on fertility or pregnancy outcomes (40). In fact, some studies have suggested that COVID-19 vaccines may have a protective effect on pregnancy, by reducing the risk of severe COVID-19 and the associated complications, such as preterm birth and stillbirth (41).

The mechanisms behind the potential effects of COVID-19 vaccines on fertility and pregnancy are not yet fully understood, but they may involve the interaction between the vaccine components and the reproductive system (42). For example, it has been hypothesized that the mRNA vaccines could potentially be taken up by the ovaries or testes, leading to the expression of the spike protein and the induction of an immune response (43). However, this hypothesis has not been supported by experimental evidence, and the biodistribution of mRNA vaccines in the body remains poorly understood (44).

Challenges in assessing long-term safety

Assessing the long-term safety of COVID-19 vaccines presents several challenges, including the limited duration of follow-up in clinical trials, the lack of a control group in real-world studies, and the potential for confounding factors, such as the effects of the pandemic itself (45). Additionally, the rapid development and deployment of COVID-19 vaccines have raised concerns about the potential for unforeseen long-term adverse effects that may not be detected in the initial studies (46).

To address these challenges, several strategies have been proposed, including the extension of clinical trial follow-up, the use of large-scale observational studies with appropriate control groups, and the establishment of long-term safety registries (47). Additionally, the use of novel technologies, such as real-time safety monitoring and machine learning algorithms, could potentially improve the detection and assessment of long-term adverse effects (48).

Recommendations for future research and surveillance

Based on the current evidence and the identified challenges, we propose the following recommendations for future research and surveillance on the adverse effects of COVID-19 vaccines:

1. Extension of clinical trial follow-up: The duration of follow-up in clinical trials of COVID-19 vaccines should be extended to at least 2-3 years to allow for the assessment of long-term safety outcomes, such as autoimmune diseases, cancer, and neurological disorders (49).
2. Large-scale observational studies: Observational studies with appropriate control groups, such as individuals who have not received COVID-19 vaccines or those who have received other vaccines, should be conducted to assess the long-term safety of COVID-19 vaccines in real-world settings (50).
3. Long-term safety registries: National and international registries should be established to collect and analyze data on the long-term safety of COVID-19 vaccines, including the incidence and characteristics of adverse events, the duration of follow-up, and the potential risk factors (51).
4. Standardized case definitions: Standardized case definitions for adverse events following COVID-19 vaccination should be developed and implemented to ensure the consistency and comparability of safety data across different studies and surveillance systems (52).
5. Real-time safety monitoring: Real-time safety monitoring systems, such as the Vaccine Adverse Event Reporting System (VAERS) in the United States, should be strengthened and expanded to allow for the rapid detection and investigation of potential safety signals (53).
6. Machine learning algorithms: Machine learning algorithms should be developed and validated for the analysis of large-scale safety data to improve the efficiency and accuracy of safety signal detection and assessment (54).
7. Transparent communication: Transparent and timely communication of safety data and analyses should be ensured to maintain public trust in COVID-19 vaccines and to facilitate informed decision-making by individuals and healthcare providers (55).

Conclusion

The short-term and long-term adverse effects of COVID-19 vaccines are a critical area of research and surveillance, given the global scale of vaccination efforts and the potential impact on public health. While the current evidence suggests that the benefits of COVID-19 vaccines outweigh the risks, ongoing monitoring and assessment of safety outcomes are essential to ensure the continued safety and effectiveness of these vaccines.

This review article has summarized the current evidence on the adverse effects of COVID-19 vaccines, including local and systemic reactions, allergic reactions, thrombosis with thrombocytopenia syndrome, and Guillain-Barré syndrome, as well as the potential long-term effects on autoimmunity, antibody-dependent enhancement, vaccine-associated enhanced respiratory disease, and fertility and pregnancy. We have also discussed the challenges in assessing long-term safety and provided recommendations for future research and surveillance.

As the global vaccination efforts continue and new vaccines are developed and deployed, it is crucial to maintain a robust and transparent safety monitoring system, to detect and investigate potential adverse effects in a timely and efficient manner. Only through ongoing research and surveillance can we ensure the safety and effectiveness of COVID-19 vaccines and maintain public trust in this critical public health intervention.

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